NM_001318890.3:c.1424C>T

Variant names:

• chr16-20627192-G-A
• NM_001318890.3:c.1424C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001318890.3(ACSM1):​c.1424C>T​(p.Ser475Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ACSM1 NM_001318890.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.53
• Publications: 0 publications found

Genes affected

ACSM1 (HGNC:18049): (acyl-CoA synthetase medium chain family member 1) Enables CoA-ligase activity. Predicted to be involved in acyl-CoA metabolic process and fatty acid biosynthetic process. Located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACSM3 (HGNC:10522): (acyl-CoA synthetase medium chain family member 3) Enables butyrate-CoA ligase activity. Predicted to be involved in acyl-CoA metabolic process and fatty acid biosynthetic process. Located in mitochondrion. Implicated in IgA glomerulonephritis. Biomarker of ulcerative colitis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318890.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSM1	NM_001318890.3	MANE Select	c.1424C>T	p.Ser475Phe	missense	Exon 11 of 14	NP_001305819.1	Q08AH1-1
	ACSM1	NM_052956.3		c.1424C>T	p.Ser475Phe	missense	Exon 10 of 13	NP_443188.2	Q08AH1-1
	ACSM1	NR_134918.2		n.1263+64C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSM1	ENST00000520010.6	TSL:1 MANE Select	c.1424C>T	p.Ser475Phe	missense	Exon 11 of 14	ENSP00000428047.1	Q08AH1-1
	ACSM1	ENST00000307493.8	TSL:1	c.1424C>T	p.Ser475Phe	missense	Exon 10 of 13	ENSP00000301956.3	Q08AH1-1
	ACSM1	ENST00000519745.5	TSL:1	n.*580+64C>T		intron	N/A	ENSP00000428650.1	Q08AH1-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399392 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 693976

African (AFR) AF: 0.00 AC: 0 AN: 29326

American (AMR) AF: 0.00 AC: 0 AN: 35172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24256

East Asian (EAS) AF: 0.00 AC: 0 AN: 33890

South Asian (SAS) AF: 0.00 AC: 0 AN: 74114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086386

Other (OTH) AF: 0.0000173 AC: 1 AN: 57930

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Benign	0.0056	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.016
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.59
MutPred		0.87		Loss of glycosylation at S475 (P = 0.0548)
MVP		0.66
MPC		0.44
ClinPred		0.95	D
GERP RS		2.3
Varity_R		0.79
gMVP		0.72
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr16-20638514;